Arylthiophene compounds, methods of making and using the same

Abstract

The application belongs to the technical field of medicines, and relates to arylthiophene compounds, a preparation method and application thereof. The structural general formula of the arylthiophene compounds and pharmaceutically acceptable salts is shown as general formula I. The arylthiophene compound provided by the application has low preparation cost, and is simple and easy to implement. The arylthiophene compound provided by the application can be used as a vascular endothelial growth factor receptor 2 (VEGFR-2) kinase inhibitor, can be used for preparing a medicine for treating or preventing a tumor disease related to the vascular endothelial growth factor receptor 2 kinase, and has good application value and development and application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to arylthiophene compounds, their preparation methods, and applications. Background Technology

[0002] Cancer is one of the most common causes of death, resulting from the misexpression of proto-oncogenes in the human body, leading to uncontrolled cell proliferation. With the development of molecular biology techniques, the pathogenesis of cancer is gradually being elucidated, and a series of different targets are being discovered.

[0003] Molecular targeted therapy for tumors utilizes cancer-related molecules as targets to bind drugs, antibodies, and other effective components to cancer cells, thereby achieving tumor treatment. Due to its advantages in localization and directionality, molecular targeted therapy can reduce drug dosage, improve efficacy, and reduce adverse drug reactions, making it a hot topic in the field of tumor treatment (Li Jianji, Yang Zhe, Huang Zansong. Basic and clinical research progress in molecular targeted therapy for primary liver cancer. World Chinese Journal of Gastroenterology, 2019, 27(10):643-650). Among targeted drug therapies, targeted inhibitors have greater advantages: they can avoid drug interactions, reduce adverse reactions, and provide comprehensive therapeutic effects (Guo T, Ma S. Recent Advances in the discovery of multitargeted tyrosine kinase inhibitors as anticancer agents. ChemMedChem, 2021, 16(4):600-620). Currently marketed targeted inhibitors mainly include:

[0004] Sorafenib inhibits tumor growth directly by suppressing the RAF-MEK-ERK signaling pathway. On the other hand, it inhibits tyrosine receptors related to angiogenesis and tumorigenesis, including VEGF-1, VEGF-2, PDGF receptors and c-Kit proto-oncogene, thereby blocking tumor angiogenesis and indirectly inhibiting tumor growth (Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008, 359(04):378-390).

[0005] Sunitinib is currently the small molecule kinase inhibitor with the most known targets, mainly CDK-2, KIT, VEGFR-2, Flt-3, etc. (Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res, 2016, 103, 26-48).

[0006] Pazopanib primarily targets PDGFRα, PDGFRβ, VEGFR-1, VEGFR-2, and VEGFR-3. Pazopanib exerts its anti-tumor effect by blocking PTK-mediated damage to tumor cell signaling, inhibiting angiogenesis and cell proliferation (Roskoski R. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol Res, 2017, 120, 116-132).

[0007] Sulfatinib primarily targets VEGFR-1, VEGFR-2, VEGFR-3, and FGFR-1, exhibiting dual activities of "anti-angiogenesis" and "immunomodulation." It inhibits the formation of new blood vessels on tumors by suppressing vascular endothelial growth factor receptor and fibroblast growth factor receptor. Simultaneously, it regulates macrophages by inhibiting colony-stimulating factor-1 receptor, improving the immune microenvironment and activating human immune function (Liao S, Li J, Gao S, et al. Sulfatinib, a novel multi-targeted tyrosine kinase inhibitor of FGFR1, CSF1R, and VEGFR1-3, suppresses osteosarcoma proliferation and invasion via dual role in tumor cells and tumor microenvironment. Front Oncol, 2023, 13:1158857). Summary of the Invention

[0008] The purpose of this invention is to provide an arylthiophene compound as shown in Formula I or a pharmaceutically acceptable salt thereof, and to provide a method for its preparation and its use in the preparation of medicaments for the treatment and / or prevention of tumor diseases associated with vascular endothelial growth factor receptor.

[0009]

[0010] R1 is selected from carbamoyl, cyano, and ethoxyformyl.

[0011] R2 is selectively substituted with 1-2 substituents selected from hydrogen, methyl, methoxy, trifluoromethyl, halogen, acetamyl, 3,4-ethylenedioxy, and 3,4-propanedioxy.

[0012] The arylthiophene compounds mentioned are specifically selected from the following compounds:

[0013] 4-Phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0014] 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0015] 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0016] 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0017] 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0018] 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0019] 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0020] 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0021] 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0022] 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0023] 4-(2-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0024] 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0025] 4-(4-trifluoromethylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0026] 4-(3,5-Difluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0027] 4-(3-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide;

[0028] 1-(3-cyano-4-phenyl-thiophen-2-yl)-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0029] 1-[3-cyano-4-(3-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0030] 1-[3-cyano-4-(4-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0031] 1-[3-cyano-4-(4-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0032] 1-[3-cyano-4-(2,4-dimethoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0033] 1-[3-cyano-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0034] 1-[3-cyano-4-(4-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0035] 1-[3-cyano-4-(3,4-dihydro-2H-benzo[b][1,4]dioxane] -7-yl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0036] 1-[3-cyano-4-(3-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0037] 1-[3-cyano-4-(2-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0038] 1-[3-cyano-4-(4-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0039] 1-[3-cyano-4-(4-fluorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0040] 1-[3-cyano-4-(2-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0041] 1-[3-cyano-4-(3-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0042] 1-[3-cyano-4-(4-trifluoromethylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0043] 1-[3-cyano-4-(4-acetamidophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea;

[0044] 4-Phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0045] 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0046] 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0047] 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0048] 4-(2,4-Dimethoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0049] 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0050] 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0051] 4-(3,4-dihydro-2H-benzo[b][1,4]dioxane) -7-yl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureo}thiophene-3-carboxylic acid ethyl ester;

[0052] 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0053] 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0054] 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0055] 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0056] 4-(4-acetamidophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0057] 4-(2-Methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester;

[0058] 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester.

[0059] This invention provides a method for preparing the above-mentioned compound, wherein the preparation method is selected from method I, method II, and method III;

[0060] Compound 1 was dissolved in malononitrile in dichloromethane and reacted in the presence of TiCl4. After the reaction was complete, the mixture was separated and purified to obtain intermediate 2. Intermediate 2 was reacted with S and diethylamine in ethanol. After the reaction was complete, the mixture was separated and purified to obtain intermediate 3. Intermediate 3 was reacted with phenyl[3-(pyrrolidone-1-yl)propyl]carbamate and KOH in DMSO. After the reaction was complete, the mixture was separated and purified to obtain the final product.

[0061] Method II:

[0062] Intermediate 3 was hydrolyzed in 80% sulfuric acid to obtain intermediate 4; intermediate 4, phenyl[3-(pyrrolidone-1-yl)propyl]carbamate, and KOH were reacted in DMSO, and the final product was obtained after separation and purification after the reaction was completed.

[0063] Method III:

[0064] Compound 1 and ethyl cyanoacetate were reacted in dichloromethane in the presence of TiCl4. After the reaction was complete, the mixture was separated and purified to obtain intermediate 5. Intermediate 5 was reacted in ethanol with S and diethylamine. After the reaction was complete, the mixture was separated and purified to obtain intermediate 6. Intermediate 6, phenyl[3-(pyrrolidone-1-yl)propyl]carbamic acid and KOH were reacted in DMSO. After the reaction was complete, the mixture was separated and purified to obtain the final product.

[0065] The preparation route is shown below:

[0066]

[0067] This invention provides the use of the arylthiophene compounds or pharmaceutically acceptable salts thereof in the preparation of vascular endothelial growth factor receptor 2 kinase inhibitors.

[0068] This invention provides the use of the above-mentioned arylthiophene compounds or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0069] The present invention provides a pharmaceutical composition comprising the arylthiophene compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0070] This invention provides the use of the above-mentioned pharmaceutical composition in the preparation of vascular endothelial growth factor receptor 2 kinase inhibitors.

[0071] This invention provides the use of the above-described pharmaceutical composition in the preparation of drugs for treating tumors.

[0072] Furthermore, the tumors mentioned above are selected from lung cancer, colorectal cancer, prostate cancer, and breast cancer.

[0073] The term "pharmaceutically acceptable salt" refers to a conventional acid addition salt or base addition salt formed with a non-toxic organic or inorganic acid or organic or inorganic base that retains the bioactivity and properties of the arylthiophene compound.

[0074] Further, the acid addition salt is selected from hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, hydrogen sulfate, persulfate, borate, formate, acetate, propionate, valerate, neovalerate, hexanoate, heptanoate, octanoate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cyclopropionate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelaate, acrylate, strawberry salt, crotonate, tigrinate, itaconic acid, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, tartrite, mandelate, diphenylglycolate, tropine, ascorbate, gluconate, gluconate-heptanoate, gluconate-dimethylgluconate, mannitolate, lactobionate, benzoate, phthalate, paraphthalate, furoate, nicotinate, isophthalate, etc. Nicotinate, salicylate, acetylsalicylic acid, butyrate, gallate, caffeate, ferulic acid, picrate, camphorate, camphor sulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, p-aminobenzenesulfonate, aminosulfonate, taurine, 2-hydroxyethanesulfonate, glycine salt, alanine salt, valine salt, leucine salt, isoleucine salt, phenylalanine salt, tryptophan salt, tyrosine salt, aspartic acid Salts, asparagine salts, glutamate salts, lysine salts, glutamine salts, methionine salts, serine salts, threonine salts, cysteine ​​salts, proline salts, histidine salts, arginine salts, edetate salts, pyruvate salts, α-ketoglutarate salts, alginate salts, cyclopentanepropionate salts, 3-phenylpropionate salts, 3-cyclohexylpropionic acid, 2-naphthylcarboxylate salts, 2-naphthylsulfonate salts, dihydroxynaphthylate salts, lauryl sulfate salts, glycerol phosphate salts, lauryl sulfate salts, and pectin ester salts;

[0075] Preferably, the acid used to generate the acid addition salt is selected from hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, malic acid, picric acid, citric acid, and p-aminobenzenesulfonic acid.

[0076] Furthermore, the alkali addition salt is selected from ammonium salts, alkali metal salts, alkaline earth metal salts, and salts of organic bases;

[0077] Furthermore, the alkali metal salt is selected from sodium and potassium salts; the alkaline earth metal salt is selected from calcium and magnesium salts; and the organic base salt is selected from dicyclohexylamine salt and N-methyl-D-glucosamine salt.

[0078] Furthermore, the basic nitrogen-containing groups in the arylthiophene compounds can be converted into quaternary ammonium salts through quaternization reactions, wherein the quaternization reagents are selected from lower alkyl halides, dialkyl sulfate esters, long-chain halides, and arylalkyl halides.

[0079] Further, the lower alkyl halides are specifically selected from methyl, ethyl, propyl, or butyl-substituted chlorine, bromine, and iodides; the dialkyl sulfates are specifically selected from dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; the long-chain halides are specifically selected from decyl, lauryl, myristyl, or stearoyl chlorine, bromine, and iodides; and the aralkyl halides are specifically selected from benzyl or phenethyl bromides.

[0080] The present invention also relates to pharmaceutical compositions that inhibit tyrosine kinase and serine threonine kinase, the compositions comprising the aforementioned arylthiophene compounds or derivatives thereof or pharmaceutically suitable acid addition salts thereof and pharmaceutically acceptable carriers.

[0081] "Pharmaceutical acceptable" refers to pharmaceutically acceptable carriers, excipients, prodrugs, etc., which are pharmacologically acceptable and substantially non-toxic to patients who are given the specific compound.

[0082] "Pharmaceutically active metabolites" refers to the metabolites of the arylthiophene compounds described in this invention that are pharmaceutically acceptable and effective.

[0083] The term "halogen" as used in this invention includes fluorine, chlorine, bromine, or iodine.

[0084] The above-mentioned drug composition can be administered in different ways, specifically in the form of oral, injectable, topical, inhaled, suppository, or liposomal formulations.

[0085] The arylthiophene compounds or their pharmaceutically acceptable salts described in this invention have the ability to bind to targets such as VEGFR, thereby blocking the related downstream MEK-ERK signaling pathway and inhibiting tumor cell proliferation.

[0086] Beneficial effects of this invention:

[0087] This invention provides the structures of a class of antitumor compounds with potential pharmaceutical value. The compounds of this invention have a simple preparation route, are easy to synthesize, and are low in cost. Compared with marketed drugs, they exhibit higher antitumor cell proliferation activity.

[0088] The compound provided by this invention, as an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) kinase, has the characteristics of novel structure and can be used to treat or prevent tumor diseases related to VEGFR-2 kinase, such as lung cancer, colorectal cancer, prostate cancer, and breast cancer. It has good application value and development prospects. Detailed Implementation

[0089] The invention is described in detail by way of the following examples. However, it should be understood that the invention is not limited to the specific examples described below.

[0090] Example 1: Preparation of 4-phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA01)

[0091] Step A: Preparation of 2-(1-phenylethylidene)malononitrile

[0092] Acetophenone (1.2 g, 10 mmol) and malononitrile (0.8 g, 12 mmol) were weighed and added to a round-bottom flask. 20 mL of dry dichloromethane was added, and TiCl4 (3.8 g, 20 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 30 min. 2 mL of pyridine was weighed and added dropwise to a constant-pressure dropping funnel. The mixture was allowed to stand overnight at room temperature, and the reaction was monitored by TLC until complete. 40 mL of 3 mol / L hydrochloric acid was added, and the mixture was separated. The aqueous layer was extracted with dichloromethane, and the two dichloromethane layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated to obtain 1.6 g of a yellow oily substance, with a yield of 95.2%.

[0093] Step B: Preparation of 2-amino-4-arylthiophene-3-carboxynitrile

[0094] 1.6 g (10 mmol) of 2-(1-phenylethylidene) malononitrile was dissolved in 20 mL of anhydrous ethanol. S (0.5 g, 15 mmol) was added, and the mixture was heated to reflux. Diethylamine (1.5 g, 20 mmol) was rapidly added dropwise to a round-bottom flask. The reaction was monitored by TLC until complete. Separation by column chromatography yielded 1.5 g of a yellow solid, with a yield of 75.2%.

[0095] Step C: Preparation of 2-amino-4-phenylthiophene-3-carboxamide

[0096] 1.0 g (5 mmol) of 2-amino-4-arylthiophene-3-carboxynitrile was weighed and added to a round-bottom flask. 10 mL of 80% sulfuric acid was added dropwise. The reaction was carried out at 90 °C for 2 h. The reaction was monitored by TLC and found to be complete. The reaction solution was added dropwise to ice water and the pH was adjusted to 10 with ammonia. A large amount of solid precipitated. The solid was filtered and dried to give 1.0 g of grayish-white solid, with a yield of 91.5%.

[0097] Step D: Preparation of 4-phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA01)

[0098] In a round-bottom flask, 2-amino-4-phenylthiophene-3-carboxamide (0.46 g, 2.1 mmol), phenyl[3-(pyrrolidone-1-yl)propyl]carbamate (0.8 g, 3.2 mmol), and KOH (0.25 g, 4.2 mmol) were added, followed by 10 mL of DMSO. The reaction was carried out at room temperature under nitrogen protection. TLC monitoring showed the reaction was complete. The reaction solution was added dropwise to 100 mL of water, extracted with EA, dried over sodium sulfate solution, filtered, and separated by column chromatography to give 0.4 g of a white solid (yield 49.4%); mp: 175.1–176.9 °C. 1 HNMR(400MHz,Chloroform-d)δ11.37(s,1H),7.45–7.35(m,5H),6.73(s,1H),6.43(s,1H),5.42( s,1H),5.26(s,1H),3.40–3.25(m,2H),2.73–2.44(m,6H),1.96–1.77(m,4H),1.74–1.57(m,4H). 13 C NMR (151MHz, DMSO-d6) δ136.57,127.99,127.79,126.88,112.58,54.64,52.96,38.41,26.83,25.03,22.41.ESI-HRMS m / z:calculated C 22 H 29 N3O3S([M+H)) + ):387.18548,found:387.18433.

[0099] Example 2: Preparation of 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA-02)

[0100] Following the preparation method of Example 1, 0.32 g of a white solid was obtained, with a yield of 36.4%; mp: 134.8-135.9 °C. Example 5: Preparation of 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA-03)

[0101] Following the preparation method of Example 1, 0.43 g of a pale yellow solid was obtained, with a yield of 49.4%; mp: 166.3-168.1℃; 1H NMR (600MHz, DMSO-d6) δ10.41(s,1H),7.68(s,1H),7.39(s,1H),7.29(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),6. 60(s,1H),5.88(s,1H),3.78(s,3H),3.12–3.07(m,2H),2.49–2.35(m,6H),1.72–1.66(m,4H),1.49–1.43(m,4H). 13 C NMR (151MHz, DMSO-d6) δ166.38,158.10,153.23,129.29,113.23,54.51,52.95,38.41,26.80,22.39.ESI-HRMS m / z:calculated C 21 H 28 N4O3S([M+H)) + ):417.19604,found:417.19489.

[0102] Example 4: Preparation of 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA-04)

[0103] Following the preparation method of Example 1, 0.36 g of white solid was obtained, with a yield of 42.8%; mp: 181.5-183.1℃. 1 HNMR(400MHz,Chloroform-d)δ10.96(s,1H),7.35(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2 H),6.91(s,1H),3.87–3.00(m,10H),2.63-2.59(m,2H),2.33(s,3H),1.06-1.95(m,4H). 13 C NMR (151MHz, DMSO-d6) δ158.53,138.02,131.59,128.39,127.45,112.74,45.01,38.42,20.18,10.19.

[0104] Example 5: Preparation of 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA-05)

[0105] Following the preparation method of Example 1, 0.37 g of a pale yellow solid was obtained, with a yield of 44.0%; mp: 138.2-139.7℃; 1H NMR(400MHz,Chloroform-d)δ11.41(s,1H),6.94–6.87(m,2H),6.87–6.81(m,1H),6.39(s,1H),5.49(s,1H),5 .25(s,1H),4.29(s,4H),3.36–3.25(m,2H),2.77–2.50(m,6H),1.93–1.82(m,4H),1.74–1.62(m,4H).ESI-HRMS m / z:calculated C 22 H 28 N4O4S([M+H)) + ):445.19096,found:445.18976.

[0106] Example 6: Preparation of 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA06)

[0107] Following the preparation method of Example 1, 0.39 g of a white solid was obtained, with a yield of 44.3%; mp: 211.1-213.2℃; 1 HNMR(400MHz,Chloroform-d)δ11.32(s,1H),7.41(d,J=8.4Hz,2H),7.34(d,J=8.4Hz,2H),6.67(s,1H) ,6.43(s,1H),5.20(s,2H),3.38–3.24(m,2H),2.70–2.47(m,6H),1.90–1.81(m,4H),1.71–1.61(m,4H). 13 C NMR(151MHz,DMSO-d6)δ166.21,153.25,129.60,127.61,113.02,54.67,52.97,38.41,26.85,25.09,22.42.ESI-HRMS m / z:calculatedC 20 H 25 ClN4O2S([M+H)) + ):421.14650,found:421.14587.

[0108] Example 7: Preparation of 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA07)

[0109] Following the preparation method of Example 1, 0.51 g of a pale yellow solid was obtained, with a yield of 52.5%; mp: 148.4-149.6℃;1 H NMR(400MHz,Chloroform-d)δ11.31(s,1H),7.58(t,J=1.8Hz,1H),7.53(dt,J=7.7,1.8Hz,1H),7.37–7.32(m,1H),7.31(d,J=7 .7Hz,1H),6.69(s,1H),6.46(s,1H),5.21(s,2H),3.36–3.29(m,2H),2.69–2.50(m,6H),1.92–1.83(m,4H),1.70–1.63(m,4H). 13 C NMR (151MHz, DMSO-d6) δ153.26,137.96,130.20,129.68,129.33,126.89,120.83,113.51,54.63,52.96,38.41,26.83,25.03,22.41.

[0110] Example 8: Preparation of 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA08)

[0111] Following the preparation method of Example 1, 0.47 g of a pale yellow solid was obtained, with a yield of 50.5%; mp: 167.7-169.8℃; 1 H NMR(400MHz,Chloroform-d)δ11.40(s,1H),7.68(d,J=7.9Hz,1H),7.45–7.37(m,2H),7.34–7.26(m,1H),6.56 (s,1H),6.43(s,1H),5.07(s,2H),3.36–3.29(m,2H),2.62–2.47(m,6H),1.87–1.81(m,4H),1.69–1.62(m,4H). 13 C NMR(151MHz,DMSO-d6)δ166.03,153.19,136.96,134.88,132.11,131.20,129. 66,127.50,123.21,113.46,110.81,54.69,52.98,38.41,26.84,25.13,22.42.

[0112] Example 9: Preparation of 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA09)

[0113] Following the preparation method of Example 1, 0.61 g of a white solid was obtained, with a yield of 62.8%; mp: 220.1-221.7℃; 1 HNMR(400MHz,Chloroform-d)δ11.31(s,1H),7.56(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),6.67(s,1H) ,6.44(s,1H),5.18(s,2H),3.35–3.30(m,2H),2.62–2.49(m,6H),1.90–1.81(m,4H),1.69–1.64(m,4H). 13 C NMR (151MHz, DMSO-d6) δ166.19,130.51,129.91,119.91,112.99,54.71,52.98,38.41,26.87,25.17,22.43.

[0114] Example 10: Preparation of 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA10)

[0115] Following the preparation method of Example 1, 0.44 g of a pale yellow solid was obtained, with a yield of 52.4%; mp: 187.7-190.4℃; 1 H NMR(400MHz,Chloroform-d)δ11.35(s,1H),7.42–7.34(m,2H),7.16–7.08(m,2H),6.61(s,1H),6.4 2(s,1H),5.18(s,2H),3.38–3.27(m,2H),2.73–2.38(m,6H),1.94–1.78(m,4H),1.69–1.62(m,4H).

[0116] Example 11: Preparation of 4-(2-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA11)

[0117] Following the preparation method of Example 1, 0.32 g of a pale yellow solid was obtained, with a yield of 38.1%; mp: 79.5-81.2℃; 1HNMR(400MHz,Chloroform-d)δ11.50(s,1H),7.36–7.31(m,1H),7.30–7.26(m,3H),6.55(s,1H),6.36(s,1H),5. 22(s,1H),5.06(s,1H),3.40–3.24(m,2H),2.67–2.46(m,6H),2.15(s,3H),1.88–1.77(m,4H),1.71–1.56(m,4H). 13 C NMR(151MHz,DMSO-d6)δ166.24,153.16,149.82,135.85,135.25,129.61,129. 24,127.91,125.68,112.08,54.66,52.97,38.41,26.83,25.07,22.42,18.92.

[0118] Example 12: Preparation of 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA12)

[0119] Following the preparation method of Example 1, 0.43 g of a pale yellow solid was obtained, with a yield of 45.3%; mp: 112.3-113.1℃; 1 H NMR(400MHz,Chloroform-d)δ11.43(s,1H),7.37–7.31(m,1H),7.01–6.88(m,3H),6.45(s,1H),5.49–5.20(m,3H),3.83 (s,3H),3.39–3.28(m,2H),2.84–2.63(m,6H),1.70(t,J=18.1,13.4,6.9Hz,4H),1.32–1.21(m,2H),1.03–0.77(m,2H). 13 C NMR (151MHz, DMSO-d6) δ166.28,158.43,153.25,137.11,136.38,128.85,113.58,54.44,52.89,38.41,26.71,22.34.

[0120] Example 13: Preparation of 4-(4-trifluoromethylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA13)

[0121] Following the preparation method of Example 1, 0.50 g of a pale yellow solid was obtained, with a yield of 52.6%; mp: 154.6-156.1℃.

[0122] Example 14: Preparation of 4-(3,5-difluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA14)

[0123] Following the preparation method of Example 1, 0.47 g of a pale yellow solid was obtained, with a yield of 53.4%; mp: 181.6-183.4℃; 1 H NMR(400MHz,Chloroform-d)δ11.26(s,1H),7.00–6.92(m,2H),6.89–6.82(m,1H),6.49(s,1 H),5.21(s,2H),3.37–3.28(m,2H),2.73–2.45(m,6H),1.94–1.80(m,4H),1.72–1.64(m,4H). 13 C NMR(151MHz,DMSO-d6)δ167.14,163.35,161.63,154.38,147.04,140.09,1 35.32,115.20,112.03,102.98,55.72,54.05,40.48,27.93,26.13,23.51.

[0124] Example 15: Preparation of 4-(3-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide (LA15)

[0125] Following the preparation method of Example 1, 0.39 g of a pale yellow solid was obtained, with a yield of 46.4%; mp: 171.4-173.8℃; 1 H NMR(400MHz,Chloroform-d)δ11.33(s,1H),7.44–7.35(m,1H),7.24–7.16(m,1H),7.16–6.98(m,2H),6.67(s ,1H),6.46(s,1H),5.22(s,2H),3.43–3.23(m,2H),2.83–2.34(m,6H),1.99–1.80(m,4H),1.73–1.54(m,4H). 13 C NMR (151MHz, DMSO-d6) δ166.20,153.28,135.27,129.55,124.01,114.60,113.35,54.58,52.94,38.43,26.81,24.93,22.40.

[0126] Example 16: Preparation of 1-(3-cyano-4-phenyl-thiophen-2-yl)-3-[4-(pyrrolidone-1-yl)butyl]urea (LA16)

[0127] The compound 2-amino-4-phenylthiophene-3-carboxynitrile was prepared using the method described in Example 1.

[0128] In a round-bottom flask, 0.46 g (2.3 mmol) of 2-amino-4-phenylthiophene-3-carboxynitrile, 0.9 g (3.4 mmol) of phenyl[3-(pyrrolidone-1-yl)propyl]carbamate, and 0.3 g (4.5 mmol) of KOH were added, followed by 10 mL of DMSO. The reaction was carried out at room temperature under nitrogen protection. The reaction was monitored by TLC and found to be complete. The reaction solution was added dropwise to 100 mL of water and extracted with EA. The EA layer was dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to give 0.5 g of a pale yellow solid, yield 59.5%; mp: 144.3–146.1 °C. 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=7.0Hz,2H),7.45–7.33(m,3H),6.69(s,1H ), 3.31(t,J=5.2Hz,2H),2.68–2.48(m,6H),1.92–1.80(m,4H),1.69–1.59(m,4H).

[0129] Example 17: Preparation of 1-[3-cyano-4-(3-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA17)

[0130] Following the preparation method of Example 16, 0.47 g of a pale yellow solid was obtained, with a yield of 51.1%; mp: 134.8-136.3℃; 1 H NMR(400MHz,Chloroform-d)δ7.54(d,J=2.1Hz,1H),7.49–7.45(m,1H),7.39–7.29(m,2H),6.67(s,1H),3.36(t, J=6.2Hz,2H),3.15–3.02(m,4H),2.92(t,J=7.5Hz,2H),2.09–1.99(m,4H),1.94–1.83(m,2H),1.74–1.62(m,2H).

[0131] Example 18: Preparation of 1-[3-cyano-4-(4-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA18)

[0132] Following the preparation method of Example 16, 0.39 g of a pale yellow solid was obtained, with a yield of 42.8%; mp: 158.9-161.6℃; 1 H NMR(400MHz,Chloroform-d)δ7.50(d,J=8.8Hz,2H),6.94(d,J=8.8Hz,2H),6.59(s,1H),3. 83(s,3H),3.32(t,J=6.1Hz,2H),2.80–2.60(m,6H),1.96–1.84(m,4H),1.75–1.62(m,4H).

[0133] Example 19: Preparation of 1-[3-cyano-4-(4-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidone-1-yl)butyl]urea (LA19)

[0134] Following the preparation method of Example 16, 0.43 g of a pale yellow solid was obtained, with a yield of 48.9%; mp: 170.3-173.0; 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.65 (s, 1H), 3.31 (t, J = 5.6 Hz, 2H), 2.63–2.47 (m, 6H), 2.38 (s, 3H), 1.89–1.80 (m, 4H), 1.67–1.59 (m, 4H). Example 20: Preparation of 1-[3-cyano-4-(2,4-dimethoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA20)

[0135] Following the preparation method of Example 16, 0.36 g of a pale yellow solid was obtained, with a yield of 36.7%; mp: 108.7-110.6℃; 1 H NMR(400MHz,Chloroform-d)δ7.26–7.23(m,1H),6.62(s,1H),6.55–6.49(m,2H),3.83(d,J= 4.4Hz, 6H), 3.30 (t, J = 5.8Hz, 2H), 2.74–2.52 (m, 6H), 1.92–1.83 (m, 4H), 1.71–1.58 (m, 4H).

[0136] Example 21: Preparation of 1-[3-cyano-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA21)

[0137] Following the preparation method of Example 16, 0.57 g of a pale yellow solid was obtained, with a yield of 58.2%; mp: 163.9-167.2℃; 1 H NMR (400MHz, Chloroform-d) δ7.11–7.04 (m, 2H), 6.90 (d, J = 8.3Hz, 1H), 6.59 (s, 1H), 4. 28(s,4H),3.34–3.25(m,2H),2.66–2.48(m,6H),1.91–1.79(m,4H),1.69–1.57(m,4H).

[0138] Example 22: Preparation of 1-[3-cyano-4-(4-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA22)

[0139] Following the preparation method of Example 16, 0.49 g of a pale yellow solid was obtained, with a yield of 53.3%; mp: 179.5-181.7℃; 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J=8.5Hz,2H),7.39(d,J=8.5Hz,2H),6.68(s ,1H),3.36–3.26(m,2H),2.74–2.50(m,6H),1.96–1.83(m,4H),1.74–1.61(m,4H).

[0140] Example 23: 1-[3-cyano-4-(3,4-dihydro-2H-benzo[b][1,4]dioxane] Preparation of 7-yl)thiophene-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA23)

[0141] Following the preparation method of Example 16, 0.48 g of a pale yellow solid was obtained, with a yield of 47.5%; mp: 156.0-158.6℃; 1 H NMR(400MHz,Chloroform-d)δ7.19(d,J=2.2Hz,1H),7.15(dd,J=8.3,2.2Hz,1H),7.00(d,J=8.3Hz,1H),6.61(s,1H),4. 24(t,J=5.6Hz,4H),3.36–3.27(m,2H),2.70–2.53(m,6H),2.21(p,J=5.6Hz,2H),1.92–1.82(m,4H),1.70–1.59(m,4H).

[0142] Example 24: Preparation of 1-[3-cyano-4-(3-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA24)

[0143] Following the preparation method of Example 16, 0.41 g of a white solid was obtained, with a yield of 40.2%; mp: 137.8-140.2℃; 1 HNMR(400MHz,Chloroform-d)δ7.72(t,J=1.8Hz,1H),7.54–7.46(m,2H),7.30(t,J=7.9Hz,1 H),6.71(s,1H),3.36–3.25(m,2H),2.63–2.41(m,6H),1.91–1.76(m,4H),1.69–1.55(m,4H).

[0144] Example 25: Preparation of 1-[3-cyano-4-(2-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA25)

[0145] Following the preparation method of Example 16, 0.39 g of a pale yellow solid was obtained, with a yield of 38.2%; mp: 69.6-72.6℃; 1 HNMR(400MHz,Chloroform-d)δ7.67–7.62(m,1H),7.36–7.32(m,2H),7.25–7.19(m,1H), 6.64(s,1H),3.37–3.26(m,2H),2.68–2.49(m,6H),1.90–1.74(m,4H),1.68–1.59(m,4H).

[0146] Example 26: Preparation of 1-[3-cyano-4-(4-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA26)

[0147] Following the preparation method of Example 16, 0.45 g of a pale yellow solid was obtained, with a yield of 44.1%; mp: 186.0-189.1℃; 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.5Hz,2H),7.45(d,J=8.5Hz,2H),6.69(s ,1H),3.35–3.26(m,2H),2.65–2.48(m,6H),1.91–1.81(m,4H),1.71–1.59(m,4H).

[0148] Example 27: Preparation of 1-[3-cyano-4-(4-fluorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA27)

[0149] Following the preparation method of Example 16, 0.40 g of a pale yellow solid was obtained, with a yield of 44.9%; mp: 158.6-161.1℃; 1 H NMR(400MHz,Chloroform-d)δ7.58–7.51(m,2H),7.15–7.07(m,2H),6.65(s,1H ),3.35–3.24(m,2H),2.65–2.48(m,6H),1.91–1.81(m,4H),1.69–1.57(m,4H).

[0150] Example 28: Preparation of 1-[3-cyano-4-(2-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA28)

[0151] Following the preparation method of Example 16, 0.43 g of a pale yellow solid was obtained, with a yield of 48.9%; mp: 87.3-89.1℃; 1 HNMR(400MHz,Chloroform-d)δ7.40–7.29(m,1H),7.26–7.17(m,3H),6.47(s,1H),3.32 (t,J=6.2Hz,2H),2.73–2.53(m,6H),2.28(s,3H),1.90–1.80(m,4H),1.70–1.59(m,4H).

[0152] Example 29: Preparation of 1-[3-cyano-4-(3-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA29)

[0153] Following the preparation method of Example 16, 0.44 g of a pale yellow solid was obtained, with a yield of 47.8%; mp: 139.6-141.3℃; 1 H NMR(400MHz,Chloroform-d)δ7.37–7.30(m,1H),7.18–7.11(m,2H),6.94–6.88(m,1H),6.71(s ,1H),3.85(s,3H),3.35–3.26(m,2H),2.61–2.45(m,6H),1.90–1.79(m,4H),1.67–1.58(m,4H).

[0154] Example 30: Preparation of 1-[3-cyano-4-(4-trifluoromethylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea (LA30)

[0155] Following the preparation method of Example 16, 0.38 g of a pale yellow solid was obtained, with a yield of 38.0%; mp: 191.6-193.5℃; 1 H NMR (400MHz, Chloroform-d) δ7.70–7.65(m,4H),6.76(s,1H),3.34(t,J=6.0Hz,2H),2.90–2.65(m,6H),2.00–1.90(m,4H),1.79–1.64(m,4H).

[0156] Example 31: Preparation of 1-[3-cyano-4-(4-acetamidophenyl)thiophen-2-yl]-3-[4-(pyrrolidone-1-yl)butyl]urea (LA31)

[0157] Following the preparation method of Example 16, 0.33 g of a pale yellow solid was obtained, with a yield of 34.1%; mp: 199.8-201.3℃; 1 H NMR(400MHz,Chloroform-d)δ7.61–7.50(m,4H),7.46(s,1H),6.65(s,1H),3.31(t, J=6.0Hz,2H),2.76–2.58(m,6H),2.21(s,3H),1.95–1.88(m,4H),1.78–1.71(m,4H).

[0158] Example 32: Preparation of ethyl 4-phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA32) Step A: Preparation of ethyl 2-cyano-3-phenylbut-2-enoate

[0159] Acetophenone (1.2 g, 10 mmol) and ethyl cyanoacetate (1.3 g, 12 mmol) were weighed and added to a round-bottom flask. 20 mL of dry dichloromethane was added to dissolve them. TiCl4 (3.8 g, 20 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred under ice bath conditions for 30 min. 2 mL of pyridine was weighed and added dropwise to a constant-pressure dropping funnel. The mixture was allowed to stand overnight at room temperature, and the reaction was monitored by TLC until complete. 40 mL of 3 mol / L hydrochloric acid was added, and the mixture was separated. The aqueous layer was extracted once with dichloromethane. The combined dichloromethane layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 2.1 g of a yellow oily substance, with a yield of 95.3%.

[0160] Step B: Preparation of ethyl 2-amino-4-phenylthiophene-3-carboxylate

[0161] Ethyl 2-cyano-3-phenylbut-2-enoate (2.05 g, 10 mmol) was dissolved in 20 mL of anhydrous ethanol, and sulfur (0.5 g, 15 mmol) was added. The mixture was heated to reflux, and diethylamine (1.5 g, 20 mmol) was added dropwise. The reaction was monitored by TLC and found to be complete. Separation by column chromatography yielded 1.1 g of a yellow solid, with a yield of 44.5%.

[0162] Step C: Preparation of ethyl 4-phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureo}thiophene-3-carboxylate

[0163] In a round-bottom flask, ethyl 2-amino-4-phenylthiophene-3-carboxylate (0.57 g, 2.3 mmol), phenyl[3-(pyrrolidone-1-yl)propyl]carbamate (0.9 g, 3.4 mmol), and KOH (0.3 g, 4.5 mmol) were added, followed by 10 mL of DMSO. The reaction was carried out at room temperature under nitrogen protection. The reaction was monitored by TLC and found to be complete. The reaction solution was added dropwise to 100 mL of water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and separated by column chromatography to give 0.36 g of a white solid (yield 37.9%); mp: 88.5–89.2 °C. 1 H NMR(600MHz,Chloroform-d)δ10.52(s,1H),7.34–7.27(m,5H),6.98(s,1H),6.44(s,1H),4.02(q,J=7.1Hz,2H),3.33( q,J=5.7Hz,2H),2.59–2.53(m,4H),2.50(t,J=6.4Hz,2H),1.88–1.76(m,6H),1.66–1.61(m,2H),0.89(t,J=7.1Hz,3H).

[0164] Example 33: Preparation of ethyl 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA33)

[0165] Following the preparation method of Example 32, 0.28 g of a pale yellow solid was obtained, with a yield of 27.1%; mp: 78.9-81.2℃; 1HNMR(600MHz,Chloroform-d)δ10.54(s,1H),7.31–7.22(m,3H),7.19–7.15(m,1H),7.12(s,1H),6.45(s,1H),4.05(q,J=7.1H z,2H),3.38–3.30(m,2H),2.91–2.67(m,6H),2.01–1.90(m,4H),1.82–1.73(m,2H),1.73–1.64(m,2H),0.95(t,J=7.1Hz,3H).

[0166] Example 34: Preparation of ethyl 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA34)

[0167] Following the preparation method of Example 32, 0.35 g of a pale yellow solid was obtained, with a yield of 33.4%; mp: 83.3-85.6℃; 1 HNMR(600MHz,Chloroform-d)δ10.55(s,1H),7.22(d,J=8.3Hz,2H),6.86(d,J=8.3Hz,2H),6.40(s,1H),4.05(q,J=7.2H z,2H),3.84(s,3H),3.39–3.28(m,2H),2.61–2.46(m,6H),1.93–1.82(m,4H),1.72–1.60(m,4H),0.96(t,J=7.2Hz,3H).

[0168] Example 35: Preparation of ethyl 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA35)

[0169] Following the preparation method of Example 32, 0.41 g of a pale yellow solid was obtained, with a yield of 41.8%; mp: 158.7-160.8℃; 1H NMR(600MHz,Chloroform-d)δ10.52(s,1H),7.17(d,J=7.9Hz,2H),7.12(d,J=7.9Hz,2H),6.73(s,1H),6.41(s,1H),4.08(q,J=7.1Hz,2H),3.86–3.7 1(m,2H),3.39(q,J=6.1Hz,2H),3.17–3.08(m,2H),2.92–2.75(m,2H),2.3 7(s,3H),2.18–1.91(m,6H),1.71(p,J=6.9Hz,2H),0.95(t,J=7.1Hz,3H).

[0170] Example 36: Preparation of ethyl 4-(2,4-dimethoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA36)

[0171] Following the preparation method of Example 32, 0.36 g of a pale yellow solid was obtained, with a yield of 32.7%; mp: 159.8-162.3℃; 1 H NMR(600MHz,Chloroform-d)δ10.40(s,1H),7.10(d,J=8.2Hz,1H),6.53(s,1H),6.47(d d,J=8.2,2.4Hz,1H),6.44(d,J=2.4Hz,1H),6.41(s,1H),4.04(q,J=7.1Hz,2H),3.84(s ,3H),3.69(s,3H),3.42–3.33(m,2H),3.18–3.07(m,2H),2.88–2.79(m,2H),2.27–2.17 (m,2H),2.15–2.04(m,4H),2.03–1.95(m,2H),1.75–1.66(m,2H),0.93(t,J=7.1Hz,3H).

[0172] Example 37: Preparation of ethyl 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA37)

[0173] Following the preparation method of Example 32, 0.29 g of a pale yellow solid was obtained, with a yield of 30.8%; mp: 188.3-191.2℃.

[0174] Example 38: Preparation of ethyl 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureo}thiophene-3-carboxylate (LA38)

[0175] Following the preparation method of Example 32, 0.35 g of a pale yellow solid was obtained, with a yield of 33.9%; mp: 178.6-180.8℃; 1 H NMR(600MHz,Chloroform-d)δ10.54(s,1H),7.29(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),6.84(s,1H),6.42(s,1H),4.08(q,J=7 .1Hz,2H),3.75–3.16(m,6H),3.14–3.07(m,2H),2.21–2.09(m,4H),2.04–1.96(m,2H),1.76–1.66(m,2H),0.96(t,J=7.1Hz,3H).

[0176] Example 39: 4-(3,4-dihydro-2H-benzo[b][1,4]dioxane) Preparation of ethyl thiophene-3-carboxylate (LA39) (-7-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylate

[0177] Following the preparation method of Example 32, 0.49 g of a white solid was obtained, with a yield of 43.4%; mp: 227.1-230.5℃.

[0178] Example 40: Preparation of ethyl 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA40)

[0179] Following the preparation method of Example 32, 0.43 g of a pale yellow solid was obtained, with a yield of 38.1%; mp: 101.4-103.1℃; 1 H NMR(600MHz,Chloroform-d)δ10.54(s,1H),7.46–7.39(m,2H),7.24–7.15(m,3H),6.45(s,1H),4.05(q,J=7.1 Hz,2H),3.34(t,J=6.2Hz,2H),2.89–2.62(m,6H),2.00–1.88(m,4H),1.77–1.63(m,4H),0.96(t,J=7.1Hz,3H).

[0180] Example 41: Preparation of ethyl 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA41)

[0181] Following the preparation method of Example 32, 0.40 g of a pale yellow solid was obtained, with a yield of 35.4%; mp: 153.4-155.6℃; 1 H NMR(600MHz,Chloroform-d)δ10.48(s,1H),7.55(d,J=8.0Hz,1H),7.32–7.25(m,2H),7.20–7.13(m,1H),7.05(s,1H),6.42( s,1H),4.06–3.88(m,2H),3.42–3.26(m,2H),2.77–2.53(m,6H),1.95–1.84(m,4H),1.75–1.59(m,4H),0.81(t,J=7.1Hz,3H).

[0182] Example 42: Preparation of ethyl 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA42)

[0183] Following the preparation method of Example 32, 0.47 g of a pale yellow solid was obtained, with a yield of 41.6%; mp: 96.1-98.5℃; 1 HNMR(600MHz,Chloroform-d)δ10.49(s,1H),7.43(d,J=8.2Hz,2H),7.15(d,J=8.2Hz,2H),6.41(s,1H),4.04(q, J=7.2Hz,2H),3.35–3.28(m,2H),2.67–2.47(m,6H),1.90–1.77(m,4H),1.71–1.59(m,4H),0.94(t,J=7.2Hz,3H).

[0184] Example 43: Preparation of ethyl 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA43)

[0185] Following the preparation method of Example 32, 0.21 g of a pale yellow solid was obtained, with a yield of 21.2%; mp: 167.8-169.1℃; 1 H NMR(600MHz,Chloroform-d)δ10.53(s,1H),7.26–7.20(m,2H),7.04–6.97(m,2H),6.41(s,1H),4.03(q,J=7. 1Hz,2H),3.38–3.27(m,2H),2.76–2.53(m,6H),1.95–1.82(m,4H),1.75–1.61(m,4H),0.93(t,J=7.1Hz,3H).

[0186] Example 44: Preparation of ethyl 4-(4-acetamidophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA44)

[0187] Following the preparation method of Example 32, 0.37 g of a pale yellow solid was obtained, with a yield of 34.2%; mp: 83.7-85.8℃; 1 HNMR(600MHz,Chloroform-d)δ10.52(s,1H),7.60(s,1H),7.48(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),6.40(s,1H),4.03( q,J=7.1Hz,2H),3.32(s,2H),2.67–2.53(m,8H),2.20(s,3H),1.90–1.81(m,4H),1.70–1.61(m,4H),0.94(t,J=7.1Hz,3H).

[0188] Example 45: Preparation of ethyl 4-(2-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureo}thiophene-3-carboxylate (LA45)

[0189] Following the preparation method of Example 32, 0.33 g of a pale yellow solid was obtained, with a yield of 33.7%; mp: 196.7-199.6℃; 1 H NMR(600MHz,Chloroform-d)δ10.54(s,1H),7.23–7.18(m,1H),7.16–7.08(m,3H),6.96(s,1H),6.35(s,1H),3.99–3.85(m,2H),3.40–3.32 (m,2H),3.08–2.92(m,4H),2.89–2.81(m,2H),2.07(s,3H),2.05–1.97(m,4H),1.88–1.80(m,2H),1.73–1.64(m,2H),0.76(t,J=7.2Hz,3H).

[0190] Example 46: Preparation of ethyl 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylate (LA46)

[0191] Following the preparation method of Example 32, 0.41 g of a pale yellow solid was obtained, with a yield of 40.2%; mp: 125.1-127.1℃; 1H NMR(600MHz,Chloroform-d)δ10.51(s,1H),7.24–7.18(m,1H),6.89–6.81(m,3H),6.45(s,1H),4.04(q,J=7.1Hz,2 H),3.81(s,3H),3.37–3.32(m,2H),2.94–2.68(m,6H),2.02–1.91(m,4H),1.80–1.65(m,4H),0.92(t,J=7.1Hz,3H).

[0192] Table 1. Comparison of Compound Structure Names

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199] Example 47: Inhibitory activity of the test compound on the proliferation of A549, MCF7, HCT-116, and PC3 cells

[0200] (1) Experimental materials

[0201] Cell lines: Lung cancer A549, breast cancer MCF7, colorectal cancer HCT-116, and prostate cancer PC3 cells were seeded in 96-well plates at densities of 1500, 2200, 800, and 2000 cells / well, respectively, with 100 μL per well, and used after 24 h.

[0202] Target compounds numbered LA01-LA46: dissolved in DMSO, diluted with culture medium to prepare 7 different concentrations of 100μM, 50μM, 20μM, 10μM, 5μM, 2.5μM, and 1.25μM, and stored at -20℃ for later use. The final concentration of DMSO in the culture medium was less than 0.1%.

[0203] Positive control drug: sorafenib.

[0204] MTT: Dissolve in PBS to a concentration of 2 mg / mL and store at -20°C.

[0205] (2) Experimental methods

[0206] The antitumor proliferation activity of A549, MCF7, HCT116, and PC3 cells was evaluated using the MTT assay. A549, HCT116, and PC3 cell lines were cultured on RPMI 1640 medium containing 10% fetal bovine serum (FBS), while the MCF-7 cell line was cultured on DMEM medium containing 10% FBS. When cells reached 80-90% confluence, they were confluent and passaged for no more than 20 passages, then allowed to acclimatize for 24 hours before further treatment. These cells were then placed in 96-well plates and cultured overnight in a humidified environment at 37°C with 5% CO2. After 24 hours, different concentrations of the invention's representative compound were added. After another 24 hours of culture, MTT (2 mg / mL) was added, and the cells were cultured for another 4 hours. The culture medium was removed, and the crystals were dissolved in DMSO. The absorbance was measured at 570 nm using a microplate reader (TECANSPECTRA, WetDar, Germany). The cell growth inhibition rate was calculated using the formula: Cell growth inhibition rate = (1 - OD value of drug group / OD value of control group) × 100%. A logarithmic curve was plotted between different concentrations of the test compound and its cell inhibition rate to calculate the corresponding IC50 of the test compound. 50 Values ​​were determined according to the methods described above for representative compounds of the present invention.

[0207] Table 2. Inhibitory activity of the tested compounds against tumor cell proliferation (IC50) 50 (μM)

[0208]

[0209]

[0210]

[0211] Of the 46 compounds obtained above, most showed good inhibitory activity against tumor cell proliferation in HCT116, A549, PC3, and MCF7 cell lines. Among them, compounds LA05, LA06, LA09, LA16, LA17, LA19, LA22, LA26, and LA30 showed significant IC50 activity against HCT116 cell line. 50 The IC50 value for LA30 is lower than that for the positive control drug sorafenib. 50 The concentration reached 2.51 ± 0.12 μM; compounds LA17, LA19, LA30, LA33, LA35, and LA40 showed IC50 values ​​against MCF7 cell lines. 50 The IC50 of LA17 was lower than that of the positive control drug sorafenib. 50The concentration reached 3.97 ± 0.12 μM; compounds LA03, LA09, LA13, LA16, LA17, and LA18 showed IC50 values ​​against PC3 cell lines. 50 The IC50 of LA09 was lower than that of the positive control drug sorafenib. 50 The concentration reached 2.96 ± 0.13 μM; compounds LA06, LA09, LA38, LA41, and LA45 showed IC50 values ​​against A549 cell line. 50 The IC50 of LA09 was lower than that of the positive control drug sorafenib. 50 It reached 2.22±0.19μM.

[0212] Example 48: Test compound inhibits VEGFR-2 in vitro activity

[0213] (1) Experimental materials

[0214] VEGFR-2, Active (0.1 μg / μl), SignalChem, Catalog No.: K01-11G

[0215] Poly(4:1Glu, Tyr) Peptide (1 mg / ml), SignalChem, Catalog No.: P61-58

[0216] KinaseAssay Buffer III, Signal Chem, Catalog No.: K03-09

[0217] DTT, Aladdin, Product Code: D104859-5g

[0218] ADP-Glo TM KinaseAssay, Promega, Product Code: V9101

[0219] DMSO, Chinese medicine, product number: 300724187. Staurosporine, ceramic, product number: T6680

[0220] 384well small volume white plate, Greiner, item number: 7840759. Envison, PerkinElmer

[0221] (2) Experimental steps

[0222] Thaw VEGFR-2 enzyme, Poly(4:1 Glu, Tyr) Peptide, kinase assay buffer III (5X buffer), DTT (2M), and ATP (10mM) on ice, and keep all of these reagents on ice throughout the experiment.

[0223] Prepare a 1X buffer by mixing 5X buffer with deionized water and add DTT to it. The concentration of DTT in the 1X buffer is 50 μM.

[0224] Add 1 μl / well of the 5X test compound to a white microplate and centrifuge at 1000 rpm for 1 minute. Positive control wells (1% DMSO): 1 μl / well of 1X buffer containing 5% DMSO. Blank control wells: 1 μl / well of 1X buffer containing 5% DMSO. After complete thawing of the VEGFR-2 enzyme, dilute the VEGFR-2 enzyme to 0.75 ng / μl with 1X buffer, and add 2 μl / well to each white microplate. At this point, the amount of VEGFR-2 enzyme in each well is 1.5 ng. Add 2 μl / well of 1X buffer to each blank control well.

[0225] Prepare a Poly(4:1Glu, Tyr) Peptide / ATP mixture. Add 2 μl / well of the Poly(4:1Glu, Tyr) Peptide / ATP mixture to a white microplate. The concentration of Poly(4:1Glu, Tyr) Peptide is 0.2 mg / ml, and the concentration of ATP is 50 μM. After adding the ATP, centrifuge the microplate at 1000 rpm for 1 minute. After centrifugation, attach a membrane to the microplate, press it firmly, and incubate at 25°C for 1 hour.

[0226] Equilibrate the ADP-Glo™ reagent and Kinase Detection-related reagents required for the Promega kit to room temperature, and mix the Kinase Detection buffer and Kinase Detection Substrate according to the instructions for use.

[0227] After incubation, add 5 μl / well of ADP-Glo™ reagent to a white microplate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. Add 10 μl / well of Kinase Detection mixture to a microplate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 30 minutes. Perform chemiluminescence detection on a plate reader and read the luminescence value (RLU). The inhibition rate of the test compound against VEGFR-2 enzyme is calculated using the following formula:

[0228] Inhibition%=(RLU(Sample)-RLU(1%DMSO)) / (RLU(Blank)-RLU(1%DMSO))×100%.

[0229] Table 3. Inhibition of VEGFR-2 activity by the test compounds at different concentrations (inhibition rate, %)

[0230]

[0231]

[0232] Among the tested compounds, all compounds showed varying degrees of inhibitory activity against VEGFR-2 enzyme. Compound LA09 exhibited the strongest inhibitory effect on VEGFR-2 enzyme at a concentration of 10 μM, with an inhibition rate of 99.28%, while compound LA05 showed the strongest inhibitory effect on VEGFR-2 enzyme at a concentration of 1 μM, with an inhibition rate of 96.15%.

[0233] Formulation Examples

[0234] The following formulation examples are merely illustrative of the scope of protection of the present invention and are not intended to limit it in any way. The active compounds mentioned in the following examples refer to compounds LA01-LA46 obtained in the above examples.

[0235] Example 49: Tablet Formulation

[0236] The active compound is 25-1000 mg, starch is 45 mg, microcrystalline cellulose is 35 mg, polyvinylpyrrolidone (10% aqueous solution) is 4 mL, sodium carboxymethyl cellulose is 4.5 mg, magnesium stearate is 0.5 mg, and talc is 1 mg.

[0237] Example 50: Suspension Formulation

[0238] 0.1-1000 mg of active compound, 50 mg of sodium carboxymethyl cellulose, 1.25 mg of syrup, 0.1 mg of sodium benzoate, 25 mg of flavoring agent, 5 mg of coloring agent, and 5 mL of pure water.

[0239] Example 51: Aerosol Formulation

[0240] 0.25 mg of active compound, 25-75 mL of ethanol, and 70 mg of propellant 22 (dichlorofluoromethane).

[0241] Example 52: Suppository Formulation

[0242] 250 mg of active compound and 2000 mL of saturated fatty acid glycerides.

[0243] Example 53: Injectable Formulation

[0244] 50 mg of the active compound, 1000 mL of isotonic salt solution.

[0245] Example 54: Ointment Formulation

[0246] 0.025g of micronized active compound, 10g of liquid paraffin, and soft white wax to a total of 100g.

[0247] Example 55: Ointment Formulation

[0248] 0.025g of active compound, 5g of propylene glycol, 5g of sorbitan sesquioleate, 10g of liquid paraffin, and soft white wax to 100g.

[0249] Example 56: Water-in-oil cream formulation

[0250] 0.025g of active compound, 5g of cetyl alcohol, 5g of glyceryl monostearate, 10g of liquid paraffin, 2g of cetyl alcohol polyoxyethylene ether, 0.1g of citric acid, 0.2g of sodium citrate, 35g of propylene glycol, and water to 100g.

[0251] Example 57: Water-in-oil cream formulation

[0252] 0.025g of micronized active compound, 15g of soft white wax, 5g of liquid paraffin, 5g of cetyl alcohol, 2g of Sorbimacrogolstearate (Tween 65 of a specific pharmaceutical excipient grade), 0.5g of dehydrated sorbitan monostearate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100g.

[0253] Example 58: Oil-in-water cream formulation

[0254] 0.025g of active compound, 35g of soft white wax, 5g of liquid paraffin, 5g of dehydrated sorbitol sesquioleate, 0.2g of sorbic acid, 0.1g of citric acid, 0.2g of sodium citrate, and water to 100g.

[0255] Example 59: Lotion Formulation

[0256] 0.25 g of active compound, 0.5 mL of isopropanol, 3 mg of carboxyvinyl polymer, 2 mg of NaOH, and water to 1 g.

[0257] Example 60: Formulation of a suspension for injection

[0258] 10 mg of active compound, 7 mg of sodium carboxymethyl cellulose, 7 mg of NaCl, 0.5 mg of polyoxyethylene (20) dehydrated sorbitan monooleate, 8 mg of benzyl alcohol, and sterile water to 1 mL.

[0259] Example 61: Aerosol Formulation for Oral and Nasal Inhalation

[0260] The active compound was 0.1% w / w, sorbitan trioleate was 0.7% w / w, trichlorofluoromethane was 24.8% w / w, dichlorotetrafluoroethane was 24.8% w / w, and dichlorodifluoromethane was 49.6% w / w.

[0261] Example 62: Formulation of atomizing solution

[0262] 7 mg of the active compound, 5 mg of propylene glycol, and water were added to a final volume of 10 g.

[0263] Example 63: Powder Formulation for Inhalation

[0264] Fill a capsule with a mixture of the following ingredients: 0.1 mg of micronized active compound and 20 mg of lactose. Inhale the powder using an inhalation device.

[0265] Example 64: Powder Formulation for Inhalation

[0266] The spherical powder is packed into a multi-dose powder inhaler, with each dose containing 0.1 mg of micronized active compound.

[0267] Example 65: Powder Formulation for Inhalation

[0268] The spheroidized powder is loaded into a multi-dose powder inhaler, each dose containing 0.1 mg of micronized active compound and 1 mg of micronized lactose.

[0269] Example 66: Capsule Formulation

[0270] Active compound 1.0 mg, small sugar spheres 321 mg, Aquacoat ECD 306.6 mg, acetylated tributyl citrate 0.5 mg, Tween-80 0.1 mg, Eudragit L 100-55 17.5 mg, triethyl citrate 1.8 mg, talc 8.8 mg, defoamer MMS 0.1 mg.

[0271] Example 67: Capsule Formulation

[0272] Active compound 2.0 mg, small sugar globules 305 mg, Aquocoat ECD 305.0 mg, acetylsalicylic acid tributyl ester 0.4 mg, Tween-80 0.14 mg, Eudragit NE30 D 12.6 mg, Eudragit S100 12.6 mg, talc 0.16 mg.

[0273] Example 68: Enema Formulation

[0274] Add 2 mg of active compound, 25 mg of sodium carboxymethyl cellulose, 0.5 mg of disodium EDTA, 0.8 mg of methylparaben, 0.2 mg of propylparaben, 7 mg of sodium chloride, 1.8 mg of citric acid, and 0.01 mg of Tween-80 to pure water to 1 mL.

[0275] Example 69: Formulation containing liposomes

[0276] A. Preparation of the drip formulation

[0277] Dipalmitoyl lecithin (45 mg), dimyristoyl lecithin (7 mg), dipalmitoyl phosphatidylglycerol (1 mg), and the active compound (5 mg) were placed in a glass tube. All components were dissolved in chloroform, and most of the solvent was evaporated with N2. Then, the pressure was reduced, thereby forming a lipid film on the surface of the glass tube. An aqueous solution (0.9% NaCl) was added to the lipid, and liposomes were formed at a phase inversion temperature higher than that of the lipid. The resulting suspension contained liposomes ranging in size from very small vesicles to 2 μm.

[0278] B. Preparation of inhalation formulations

[0279] Liposomes were prepared according to Example A, wherein the aqueous solution contained 10% lactose, and the ratio of lactose to lipids was 7:3. The liposome suspension was frozen with dry ice and then freeze-dried to micronize the dried product, resulting in particles with a mass-average aerodynamic diameter (MMAD) of approximately 2 μm.

[0280] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. Any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. An arylthiophene compound, characterized in that, Specifically selected from the following compounds: 4-Phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(2-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(4-trifluoromethylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(3,5-Difluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 4-(3-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxamide; 1-(3-cyano-4-phenyl-thiophen-2-yl)-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(3-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(2,4-dimethoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-chlorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(3,4-dihydro-2H-benzo[b][1,4]dioxane-7-yl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(3-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(2-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-bromophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-fluorophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(2-methylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(3-methoxyphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-trifluoromethylphenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 1-[3-cyano-4-(4-acetamidophenyl)thiophen-2-yl]-3-[4-(pyrrolidine-1-yl)butyl]urea; 4-Phenyl-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(3-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-methoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(2,4-Dimethoxyphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-chlorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(3,4-dihydro-2H-benzo[b][1,4]dioxane-7-yl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(3-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(2-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-bromophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-fluorophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(4-acetamidophenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(2-Methylphenyl)-2-{3-[4-(pyrrolidone-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester; 4-(3-methoxyphenyl)-2-{3-[4-(pyrrolidine-1-yl)butyl]ureoyl}thiophene-3-carboxylic acid ethyl ester.

2. The method for preparing the arylthiophene compound according to claim 1, characterized in that, The preparation method is selected from method I, method II, and method III; Method I: Compound 1 was dissolved in malononitrile in dichloromethane and reacted in the presence of TiCl4. After the reaction was complete, the mixture was separated and purified to obtain intermediate 2. Intermediate 2 was reacted with S and diethylamine in ethanol. After the reaction was complete, the mixture was separated and purified to obtain intermediate 3. Intermediate 3 was reacted with phenyl[3-(pyrrolidone-1-yl)propyl]carbamate and KOH in DMSO. After the reaction was complete, the mixture was separated and purified to obtain the final product. Method II: Intermediate 3 was hydrolyzed in 80% sulfuric acid to obtain intermediate 4; intermediate 4, phenyl[3-(pyrrolidone-1-yl)propyl]carbamate, and KOH were reacted in DMSO, and the final product was obtained after separation and purification after the reaction was completed. Method III: Compound 1 and ethyl cyanoacetate were reacted in dichloromethane in the presence of TiCl4. After the reaction was complete, the mixture was separated and purified to obtain intermediate 5. Intermediate 5 was reacted in ethanol with S and diethylamine. After the reaction was complete, the mixture was separated and purified to obtain intermediate 6. Intermediate 6, phenyl[3-(pyrrolidone-1-yl)propyl]carbamic acid and KOH were reacted in DMSO. After the reaction was complete, the mixture was separated and purified to obtain the final product. The preparation route is shown below: Wherein, R2 is the corresponding group at the corresponding position of the specific compound described in claim 1.

3. A pharmaceutical composition comprising the arylthiophene compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. The use of the arylthiophene compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a vascular endothelial growth factor receptor 2 kinase inhibitor.

5. The use of the pharmaceutical composition of claim 3 in the preparation of a vascular endothelial growth factor receptor 2 kinase inhibitor.

6. The use of the arylthiophene compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors.

7. Use of the pharmaceutical composition according to claim 3 in the preparation of a drug for treating tumors.

8. The application according to claim 6 or 7, characterized in that, The tumors mentioned are lung cancer, colorectal cancer, prostate cancer, and breast cancer.

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